Synthesis of Quinolinone Alkaloids via Aryne Insertions into Unsymmetric Imides in Flow

Article abstract of DOI:10.1021/acs.orglett.8b03392

A general strategy for the synthesis of 3,4-dioxygenated quinolin-2-one natural products is reported. The key step is a regioselective insertion of arynes into unsymmetric imides. When performed in continuous flow, the reaction proceeds within minutes, wh

Full text of DOI:10.1021/acs.orglett.8b03392

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Quinolinone Alkaloids via Aryne Insertions into
Unsymmetric Imides in Flow
Johannes Schwan, Merlin Kleoff, Bence Hartmayer, Philipp Heretsch,* and Mathias Christmann*
Institut fur Chemie und Biochemie, Freie Universitat Berlin, Takustr. 3, 14195 Berlin, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A general strategy for the synthesis of 3,4-dioxygenated quinolin-2-one natural products is reported. The key step
is a regioselective insertion of arynes into unsymmetric imides. When performed in continuous flow, the reaction proceeds
within minutes, while lower yields and longer reaction times are observed in batch. The resulting N-acylated 2-
aminobenzophenones were transformed to ( )-peniprequinolone, ( )-aflaquinolones E and F, ( )-6-deoxyaflaquinolone E,
( )-quinolinones A and B, and ( )-aniduquinolone C in 1−3 steps.
Scheme 1. Outline of the Work
he growing family of 3,4-dioxygenated quinolin-2-ones
Tconstitutes a valuable source of molecules with cytotoxic,
nematicidal, and antiviral activities.1,2 Biosynthetically, these
fungal secondary metabolites are derived from the non-
ribosomal peptide synthetase (NRPS) product cyclopeptin
(1), an adduct of anthranilic acid, and either O-methyl-L-
tyrosine3 or phenylalanine4 (Scheme 1a). Groll and
Hintermann demonstrated that a single enzyme, AsqJ,
catalyzes a multistep transformation of the benzodiazepine
core of 1 into the parent quinolone 2.5 Downstream processing
into the final natural products may involve prenylation (n = 0)
and double prenylation (n = 1) as well as additional oxidation
steps.6 Following this synthetic blueprint, nature has provided
a “library” of bioactive secondary metabolites3,7 from which
only yaequinolone J1, J2, and A2 have been synthesized to date
(Scheme 1b).8 Since these natural products share a common
heterocyclic core, we decided to develop a step-efficient,9
modular approach to access the entire group of these alkaloids
(Scheme 1c). Synthetically, the 3,4-dioxygenated quinolin-2-
one core (6) can be obtained by intramolecular glycolate
aldolizations.10 We speculated that aryne chemistry11 could
provide straightforward access to N-glycolated 2-amino-
benzophenones (5) and thus enable the synthesis of this
natural product family. On the basis of the contributions of
Greaney11a (acylated carbamates), Stoltz11b (symmetric
imides), and Xu11d (acrylamides), we speculated that a
selective σ-C−N insertion of in situ generated arynes (3)
into unsymmetric imides 4 could deliver 5 in a one-pot
operation.12 With these substrates, the challenge lies in the
differentiation of the two similar N-acyl groups.
conditions reported by Stoltz et al.,11b benzophenone 5a was
formed in 16% yield with only a slight preference for 5a over
As a starting point, we investigated the insertion of benzyne
Received: October 23, 2018
precursor 3a13 into the unsymmetric imide 4a. Under the
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03392
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
its constitutional isomer 7a (Table 1, entry 1). A screening of
solvents revealed that acetonitrile gave the best selectivity of
Table 2. Aryne Insertion in Flow
a
Table 1. Reaction Development in Batch
b
c
entry
solvent
T
F− source
5a:7a
5a (%)
b
entry
1
2
product
R1
R2
R3
5 (%)
1
2
3
PhMe
THF
MeCN
MeCN
MeCN
MeCN
60
60
60
80
80
80
TBAT
TBAT
TBAT
TBAT
CsF
1.3:1
2.0:1
5.7:1
4.1:1
3.7:1
4.0:1
16
18
25
35
33
20
5a
5b
5c
5d
5e
5f
H
H
H
H
OMe
Br
H
OMe
H
Me
Me
Me
Me
Me
Bn
52
60
23
35
24
40
18
30
c
3
4
5
d
4
OBn
OBn
H
OAllyl
OAllyl
d
5
de
,
c
6
KF
6
7
8
a
Reaction conditions: 4a (0.26 mmol, 1 equiv), 3a (0.39 mmol, 1.5
5g
5h
H
OMe
Me
Me
equiv), F− source (0.52 mmol, 2 equiv), solvent (2.0 mL), 16 h.
c
b
c
Ratios were determined by 1H NMR integration. Isolated yield.
a
Reaction conditions: 4 (0.20 mmol, 1 equiv, 0.1 M in MeCN), 3
(0.30 mmol, 1.5 equiv, 0.15 M in MeCN), TBAT (0.36 mmol, 1.8
equiv, 0.18 M in MeCN), 4 mL reactor volume, 65 °C. Isolated
yield. 4b (c = 0.01 M in MeCN), 3a−c (c = 0.015 M in MeCN),
d
e
Conducted for 4 h. 18-crown-6 (1 equiv) and 4 Å mol sieves were
used as additives.
b
c
5.7:1 (entry 3). Among the different fluoride sources,
tetrabutylammonium difluorotriphenylsilicate (TBAT) gave
the highest yield of 5a with 35% and an isomeric ratio of 4.1:1
(entry 4). Upon extending the reaction time, 7a undergoes
slow thermal decomposition, leading to a slightly increased
isomer ratio in favor of 5a. Furthermore, it turned out that
imide 4a also slowly decomposes to benzamide at elevated
temperatures and under basic conditions.
Because of superior heat and mass transfer, reactions
performed in flow can significantly be accelerated. Therefore,
intermediates such as 8 often react with higher selectivity and
yield, enabling reactions that are otherwise impossible.14
Surprisingly, only a few examples are reported, where arynes
are generated and used in a flow reactor.15
To suppress thermal imide decomposition by shortening the
reaction time, a flow protocol seemed promising. Because of its
high solubility, TBAT is a better fluoride source for flow
reactions than cesium fluoride. An optimization of reaction
time, temperature, and stoichiometry (see Supporting
Information for details) increased the yield of 5a from 25%
in batch (Table 1, entry 3) to 52% when conducted at 65 °C
with 1.5 equiv of 3a at a residence time of 4 min (Table 2,
entry 1). Under these conditions, a regioselectivity of 2.9:1
(5a:7a) was observed.
TBAT (c = 0.018 M in MeCN).
quinolinone B (10).19c In agreement with the literature
reports,11a,b,20 we also observed significantly lower yields
with those substrates. Thus, when using 3-O-benzyl and 3-O-
allyl substituted aryne precursors 3b and 3c, the yield dropped
to 35% and to 18% (Table 2, entries 4, 5, 7, 8). The insertion
was also performed with 4-bromo substituted imide 4c to
access an unnatural quinolinone derivative with a handle for
cross-coupling chemistry as well as O-benzyl substituted imide
4d to access aflaquinolone F (11).18 For imide 4b, the reaction
had to be diluted by a factor of 10 due to limited solubility of
4b in acetonitrile (Table 2, entries 2, 5, and 8). In all cases,
benzophenones 5a−h were obtained as the major product
along with unreacted imides 4a−d.
With the benzophenones 5a−h in hand, we next investigated
an intramolecular aldo reaction10 to forge the 3,4-dioxygenated
quinoline-2-one core. Using an excess of potassium tert-
butoxide in tetrahydrofuran at 0 °C, the quinolinones 6a−g
were obtained as single diastereomers (Scheme 2). Following
this procedure, the natural products ( )-6-deoxyaflaquinolone
E (6a)21 and ( )-quinolinone A (6b)19c were prepared in 91%
and 84% yields, respectively.
Using the optimized conditions, a collection of substituted
arynes and imides was reacted. According to the proposed
mechanism, the aryne insertion proceeds via intermediacy of
8.11a,b,16 Greaney et al.11a showed that a major byproduct
results from premature protonation of 8. Remarkably, under
flow conditions, even the use of wet acetonitrile did not
increase the amount of byproduct, thus rendering the flow
process more sustainable. As arynes bearing a 3-alkoxy
substituent have been reported to undergo regioselective
nucleophilic attack in the meta-position,17 we expected the
resulting benzophenones to provide us access to the 5-
hydroxyquinolinone cores present in aflaquinolone E (9)18 and
Cyclization of 5d, 5e, and 5f delivered the benzyl protected
quinolinones 6d, 6e, and 6f, which were subjected to
hydrogenolysis to afford the natural products ( )-aflaquino-
lone E (9), F (11),18 and ( )-quinolinone B (10)19c in up to
82% yield over two steps. Quinolinones 6g and 6h underwent
Claisen rearrangement at 150 °C in 1,2-dichlorobenzene for
10 h to give 12a and 12b in 71% and 63% yield, respectively
(Scheme 3).21 At higher temperature and prolonged reaction
time, elimination of the tertiary alcohol was observed. Grubbs’
olefin cross metathesis22 of 12a and 2-methylbut-2-ene
(excess) using Umicore M71SIMes as catalyst gave ( )-ani-
duquinolone C (13a)23 in 81% yield, whereas ( )-penipre-
B
DOI: 10.1021/acs.orglett.8b03392
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
molecular aldolization. A flow protocol for the aryne insertion
was developed, which gave access to N-glycolated 2-amino-
benzophenones within minutes. By this not immediately
evident, yet powerful disconnection, the quinolinone natural
products peniprequinolone, aflaquinolone E, F, quinolone A, B,
and aniduquinolone C were synthesized in three to six steps.24
Future work will focus on the synthesis of quinolinone natural
products with other side chains and higher oxidation levels.
Scheme 2. Intramolecular Aldolization
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03392.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: mathias.christmann@fu-berlin.de
*E-mail: philipp.heretsch@fu-berlin.de
ORCID
Mathias Christmann: 0000-0001-9313-2392
Notes
The authors declare no competing financial interest.
A version of this research was previously posted to ChemRxiv:
Schwan, Johannes; Kleoff, Merlin; Hartmayer, Bence;
Heretsch, Philipp; Christmann, Mathias (2018): Synthesis of
Quinolinone Alkaloids via Aryne Insertions into Unsymmetric
Imides in Flow. ChemRxiv. Preprint. Oct. 24, 2018. https://
doi.org/10.26434/chemrxiv.7241501.v1.
ACKNOWLEDGMENTS
Scheme 3. Synthesis of Aniduquinolone C and
Peniprequinolone
■
We thank Dr. Florian Bartels and Dr. Reinhold Zimmer (FU
Berlin) for helpful discussions. We also thank Umicore for a
generous donation of metathesis catalysts.
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D
DOI: 10.1021/acs.orglett.8b03392
Org. Lett. XXXX, XXX, XXX−XXX